Lee Seo-Yeon, Park Jung Hwa, Cho Kang-Hyun, Kim Huiseon, Shin Hwa Kyoung
Department of Pharmacology, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea.
Department of Biomedical Science, Wonkwang University School of Medicine, Iksan, Jeonbuk 54538, Republic of Korea.
Oncol Lett. 2022 Aug 2;24(4):328. doi: 10.3892/ol.2022.13448. eCollection 2022 Oct.
Glioblastoma multiforme (GBM) is the most frequently occurring malignant brain tumor in adults and is characterized by a high degree of vascularization. Glioblastoma cells communicate with their microenvironment and stimulate blood vessel formation to support tumor progression. It has previously been reported that isolinderalactone induces apoptosis in GBM cells and suppresses the growth of glioblastoma xenograft tumors . Furthermore, isolinderalactone has been shown to inhibit the hypoxia-driven upregulation of vascular endothelial growth factor (VEGF) in U-87 GBM cells and strongly reduce VEGF-triggered angiogenesis and . In the present study, the direct angiogenic effect of GBM and the effect of isolinderalactone on tumor angiogenesis were investigated. Culture supernatants were obtained from U-87 cells under normoxic or hypoxic conditions to provide normoxic conditioned medium (NCM) and hypoxic conditioned medium (HCM) respectively. The NCM and HCM were each used to treat to human brain microvascular endothelial cells (HBMECs), and their effects were observed using wounding migration and tube formation assays. HCM increased the migration and capillary-like tube formation of HBMECs when compared with NCM, and treatment with isolinderalactone suppressed the HCM-driven angiogenesis . Additionally, isolinderalactone decreased HCM-triggered angiogenic sprouting in HBMECs in a 3D microfluidic device after the application of an HCM-containing interstitial fluid flow. Furthermore, isolinderalactone strongly reduced HCM-triggered angiogenesis in an Matrigel plug assay in mice. These findings provide evidence of angiogenesis inhibition by isolinderalactone, and demonstrate the anti-angiogenic effect of isolinderalactone against the direct angiogenic effect of GBM tumor cells.
多形性胶质母细胞瘤（GBM）是成人中最常见的恶性脑肿瘤，其特征是高度血管化。胶质母细胞瘤细胞与其微环境相互作用，并刺激血管形成以支持肿瘤进展。此前有报道称，异嗪皮啶酮可诱导GBM细胞凋亡并抑制胶质母细胞瘤异种移植肿瘤的生长。此外，异嗪皮啶酮已被证明可抑制缺氧驱动的U-87 GBM细胞中血管内皮生长因子（VEGF）的上调，并强烈减少VEGF触发的血管生成。在本研究中，研究了GBM的直接血管生成作用以及异嗪皮啶酮对肿瘤血管生成的影响。在常氧或缺氧条件下从U-87细胞获得培养上清液，分别提供常氧条件培养基（NCM）和缺氧条件培养基（HCM）。将NCM和HCM分别用于处理人脑微血管内皮细胞（HBMECs），并使用伤口迁移和管形成试验观察其效果。与NCM相比，HCM增加了HBMECs的迁移和毛细血管样管形成，而异嗪皮啶酮处理抑制了HCM驱动的血管生成。此外，在施加含HCM的间质液流后，异嗪皮啶酮减少了3D微流控装置中HBMECs中HCM触发的血管生成芽生。此外，异嗪皮啶酮在小鼠的基质胶栓试验中强烈减少了HCM触发的血管生成。这些发现提供了异嗪皮啶酮抑制血管生成的证据，并证明了异嗪皮啶酮对GBM肿瘤细胞直接血管生成作用的抗血管生成作用。
